Labdanes and process for their preparation

ABSTRACT

Labdanes of the formula ##STR1## a process for their manufacture, pharmaceutical preparations containing an effective amount of these compounds and their use for the manufacture of a pharmaceutical preparation for treatment of cardiovascular diseases and high intraocular pressure.

This invention relates to novel pharmacologically active6/7-acyloxy-7/6-aminoacyloxy-polyoxygenated labdane derivatives and aprocess for their preparation.

The following patents/patent applications and publications relate topolyoxygenated labdanes and their derivatives.

Indian patent No. 143 875 and the corresponding U.S. Pat. No. 4,088,659,

Indian patent No. 145 926,

Indian patent No. 147 030 and the corresponding U.S. Pat. No. 4,118,508,

Indian patent No. 147 007 and the corresponding German patentapplication No. P 26 54 786.6;

Tetrahedron Letters No. 19, pp. 1669-1672, 1977, J. Chem. Soc., PerkinTrans. 1, 767, 1982. Offenlegungsschrift DE 33 46 869;

Indian patent No. 163 242 and the corresponding German patentapplication No. P 35 35 086.5; J. Med. Chem. 31, 1872, 1988.

The pharmacological properties of polyoxygenated labdanes and theirderivatives mentioned in the above prior art literature render themsuitable for use in the treatment of cardiac and circulatory diseases,hypertension, glaucoma, allergy, broncho-constriction and asimmunomodulators.

Examples of the polyoxygenated labdane derivatives of the presentinvention have not been cited in the earlier literature. Compounds ofthe prior art literature which are structurally related in part to thecompounds of the invention are the derivatives which bear a6-aminoacyloxy group in the polyoxygenated labdanes. The essentialdifference between the compounds of the invention and those of the priorart lies in the pattern of substitution at the 6- and 7-positions,namely in the compounds of the invention when one of the 6-substituentor 7-substituent is an aminoacyl group, the other is an alkoxyacyloxy oraryloxyacyloxy group, whereas in compounds of the prior art when the6-substituent is an aminoacyloxy group, the 7-substituent is only eithera hydroxy, acyloxy, or an aminoacyloxy group. This alteration instructure surprisingly alters the pharmacological profile of thecompounds, which renders them potentially more useful especially for thetreatment of glaucoma, and congestive cardiomyopathy, in contrast tocompounds of the prior art.

Accordingly the object of the present invention is to provide novelpharmacologically active polyoxygenated labdane derivatives and aprocess for their preparation.

The present invention relates to labdanes of the formula I ##STR2## inwhich R denotes vinyl, ethyl, cyclopropyl or CHOHCH₂ OH,

R₁ denotes hydrogen, a group of the formula ##STR3## A denoting OR₂, inwhich R₂ represents an alkyl group, or denoting ##STR4## X and Yrepresenting, if they are identical, hydrogen or alkyl, or, if Xrepresents hydrogen or lower alkyl, Y representing an alkyl, substitutedalkyl, cycloalkyl, aralkyl, aryl, amino or hydroxyl group, or X and Y,together with the nitrogen atom to which they are bonded, forming aheterocyclic ring which can contain a further hetero atom and can besubstituted by an alkyl or aryl group, or

R₁ may be represented by a group of the formula R₃ R₄ R₅ Si, each of R₃,R₄ and R₅ independently denoting an alkyl group,

R₆ or R₇ denotes a group of the formula ##STR5## in which m and n areintegers from 1 to 10, and R₈ and R₉ are identical or different andrepresent hydrogen or a lower alkyl group, or one of the substituentsrepresents hydrogen and the other represents a hydroxyl, thio or arylgroup, R₁₀ denotes hydrogen and R₁₁ denotes hydrogen or a hydroxyl oralkyl group, and X₁ represents hydrogen if Y₁ represents hydrogen,alkyl, substituted alkyl, alkanoyl, aryl, cycloalkyl, aralkyl, aheterocycle, amino, substituted amino, hydroxyl, acyl, dialkylaminoalkyl, carbamoyl, carboxyalkyl or carbalkoxyalkyl, or X₁ and Y₁represent, if they are identical, alkyl, substituted alkyl, aryl oraralkyl, or, if X₁ represents alkyl; Y₁ represents substituted alkyl,cycloalkyl, aralkyl or a dialkylaminoalkyl group, or X₁ and Y₁ form,together with the nitrogen atom to which they are bonded, a heterocyclewhich can contain one or more hetero atoms and be optionally substitutedonce or several times by alkyl, aryl, aralkyl, hydroxyalkyl, hydroxyl orother heterocyclic groups, and B denotes a substituted alkyl group withthe proviso that R.sub. 6 and R₇ are not simultaneously ##STR6## inwhich R₈ ro R₁₁, X₁, Y₁, m and n have the above meanings, and to theiroptical and geometric isomers and their pharmaceutically acceptable acidaddition salts.

Preferred compounds of the formula I are those in which R has theabove-mentioned meaning, preferably vinyl, R₁ represents hydrogen, R₆represents a group of the formula ##STR7## in which R₈ -R₁₁, X₁ and Y₁have the afore-mentioned meaning, and R₇ represents a group of theformula ##STR8## wherein B has the above mentioned meaning.

Especially preferred are compounds of the formula I, wherein R is vinyl,R₁ is hydrogen, R₆ is a group of the formula ##STR9## wherein m and neach are the integer 1, R₈ -R₁₁ are hydrogen, X₁ and Y₁ are C₁ -C₄-alkyl, preferably methyl or X₁ and Y₁ form together with the nitrogenatom to which they are bonded, a piperidine, morpholine or piperazinering, which may be substituted by C₁ -C₄ -alkyl, preferably methyl, andR₇ is --CO--B. wherein B is C₁ -C₄ -alkyl, preferably methyl,substituted by C₁ -C₄ -alkoxy, phenoxy or halogeno-phenoxy.

The term alkyl relates to straight chain or branched saturatedhydrocarbon radicals having 1 to 8 carbon atoms such as, for example,methyl, ethyl, propyl, 2-methylpropyl, 1-pentyl, 3-hexyl or 2-octyl andthe like. Preferred alkyl groups have 1 to 6, in particular 1 to 4,carbon atoms. Especially preferred is methyl.

Suitable examples of substituted alkyl groups are hydroxyalkyl such ashydroxyethyl, carboxyalkyl such as carboxyethyl, carbalkoxyalkyl such ascarboethoxyethyl, or halogenated alkyl. Alkoxyalkyl wherein alkoxy has1-4 carbon atoms such as methoxymethyl or ethoxymethyl, aryloxyalkylsuch as phenoxymethyl, halogenophenoxymethyl, such asp-chlorophenoxymethyl, aralkyl such as benzyl, thioalkyl such asmethylthiomethyl. Especially preferred are methoxymethyl, ethoxymethyl,phenoxy- and p-chlorophenoxy. methyl.

Suitable cycloalkyl groups are C₃ -C₇ -cycloalkyl groups, in particularcyclopentyl or cyclohexyl.

An aralkyl group is to be understood to be a phenylalkyl group,preferably phenyl-C₁ -C₃ -alkyl, for example a benzyl group in which thephenyl group can be substituted once or several times by halogen, C₁ -C₃-alkyl, C₁ -C₃ -alkoxy, nitro or trifluoromethyl.

An aryl group is to be understood to be a phenyl group which can besubstituted once or several times by substitutents such as halogen, C₁-C₃ -alkyl, C₁ -C₃ -alkoxy, nitro, amino, substituted amino ortrifluoromethyl.

An acyl group is to be understood to be C₁ -C₆ -alkanoyl, C₂ -C₆-alkenoyl, aroyl, aralkanoyl or heteroaroyl group having up to 10 carbonatoms, it being possible for one or more carbon atoms to be replaced byoxygen, nitrogen and/or sulfur.

Examples of alkanoyl groups are formyl, acetyl, propionyl, butyryl,isobutyryl, valeryl, palmityl and bromisobutyryl. The alkanoyl groupscan contain one or more double bonds, for example an acryloyl, stearylor oleoyl group. The alkanoyl groups can also contain one or more triplebonds as well as one or more double bonds. An example of alkynoyl groupof this type is the propiolyl group. A representative of aroyl groups isthe benzoyl group in which the phenyl group can be substituted once orseveral times by substituents such as C₁ -C₃ -alkyl, C₁ -C₃ -alkoxy,halogen, nitro, amino, substituted amino, and trifluoromethyl. Examplesof aralkanoyl and heteroaroyl groups are phenyl acetyl andpyridine-3-carbonyl groups.

The dialkylaminoalkyl groups are to be understood to be those in whicheach of the alkyl groups contains 1 to 6 carbon atoms, for examplediethylaminoethyl.

If X and Y or X₁ and Y₁ form, together with the nitrogen atom to whichthey are bonded, a heterocyclic ring, those which are preferred arepiperidine, pyrrolidine, morpholine, piperazine, thiomorpholine,imidazole and theophylline, each of which can optionally be substitutedin one or more positions by C₁ -C₄ -alkyl, C₁ -C₄ -alkoxy, aryl, aryl-C₁-C₄ -alkyl, hydroxyl, amino or substituted C₁ -C₄ -alkyl.

Suitable examples of the salts of the compounds according to theinvention with inorganic or organic acids are the hydrochloride,hydrobromide, sulfate, phosphate, acetate, oxalate, tartrate, citrate,maleate or fumarate.

In the formula depicted here, the various substituents are shown asconnected to the labdane nucleus in one or two modes of representation:a full line--which indicates a substituent in the β-orientation (i.e.above the plane of the molecule), and a broken line (- - -) whichindicates a substituent in the α-orientation (i.e. below the plane ofthe molecule). All the formulae are drawn in such a way that they depictthe compounds in their absolute stereochemical configuration. Where thestarting materials having a labdane nucleus are naturally occurring orare derived from natural products they have, as do the final products, alabdane nucleus in the single absolue configuration depicted here.However, the process according to the invention is also meant for thesynthesis of labdanes of the racemic series.

In addition to the optical centers of the labdane nucleus, thesubstituents thereon may also have chiral centers which contribute tothe optical properties of the compounds to the invention and allow theirseparation by conventional methods, for example by the use of opticallyactive acids. A wavy line (˜) connecting a group to a chiral centerindicates that the stereochemistry of the center is unknown, i.e. thegroup may be present in either of the possible orientations. Thisinvention embrces all the optical isomers and racemic forms of thecompounds according to the invention where such compounds have chiralcenters in addition to those of the labdane nucleus.

Some of the new, polyoxygenated labdane derivatives according to theinvention are listed in Table 1 which is as follows:

                                      TABLE 1                                     __________________________________________________________________________     ##STR10##                                                                                                       Melting                                    R.sub.6         R.sub.7        X   point (°C.)                         __________________________________________________________________________     ##STR11##      COCH.sub.2 OCH.sub.3                                                                         HCl 146-150                                     ##STR12##      COCH.sub.2 OC.sub.2 H.sub.5                                                                  HCl 249-251                                     ##STR13##      COCH.sub.2 OC.sub.6 H.sub.5                                                                  HCl 231-233                                     ##STR14##      COCH.sub.2 OC.sub.6 H.sub.4 Cl(p)                                                            HCl 226-228                                     ##STR15##      COCH.sub.2 OCH.sub.3                                                                         HCl 160                                         ##STR16##      COCH.sub.2 OC.sub.2 H.sub.5                                                                  HCl 139-141                                     ##STR17##      COCH.sub.2 OC.sub.6 H.sub.5                                                                  HCl 230                                         ##STR18##      COCH.sub.2 OC.sub.6 H.sub.4 Cl (p)                                                           HCl 256-257                                     ##STR19##      COCH.sub.2 OC.sub.2 H.sub.5                                                                  2HCl                                                                              215                                         ##STR20##      COCH.sub.2 OC.sub.6 H.sub.5                                                                  2HCl                                                                              207-208                                     ##STR21##      COCH.sub.2 OC.sub.6 H.sub.4Cl (p)                                                            2HCl                                                                              207-208                                    COCH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                                         COCH.sub.2 OCH.sub.3                                                                         HCl 238-237                                    COCH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                                         COCH.sub.2 OC.sub.2 H.sub.5                                                                  HCl 218                                        COCH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                                         COCH.sub. 2 OC.sub.6 H.sub.5                                                                 HCl 219                                        COCH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                                         COCH.sub.2 OC.sub.6 H.sub.4Cl (p)                                                            HCl 242-243                                    COCH.sub.2 OCH.sub.3                                                                          COCH.sub.2 CH.sub.2 NMe.sub.2                                                                HCl 242-243                                    COCH.sub.2 OCH.sub.3                                                                           ##STR22##     HCl 215-217                                    COCH.sub.2 OCH.sub.3                                                                           ##STR23##     HCl 194-196                                    COCH.sub.2 OCH.sub.3                                                                           ##STR24##     2HCl                                                                              206-208                                    __________________________________________________________________________

The invention also relates to a process for the preparation of the newacyllabdanes of the formula I, which comprises reaction of compounds ofthe formula II ##STR25## in which R'₁ denotes a protective group for ahydroxyl group such as the methyl ether, t-butyl ether, allyl ether,benzyl ether, trialkyl-methyl ether, trialkylsilyl ether ortetrahydropyranyl ether or esters, particularly the t-butyldimethylsilylgroup and R, R₈ -R₁₁ and X₁ and Y₁ have the above-mentioned meanings,with a mixture of an appropriate acid of the formula

    B--COOH

[wherein B denotes substituted alkyl,] preferably of the formula R₁₂ZCH₂ COOH [wherein Z is oxygen and R₁₂ is alkyl, preferably C₁ -C₄-alkyl, or aryl, preferably phenyl, which may be substituted, forexample by halogen, or a heterocycle],dicyclohexyl carbodiimide (DCC),and 4-dimethylaminopyridine in organic solvents, such as e.g. dichloromethane, DMF or ethyl acetate, at temperatures in the range of about 20°C. to 70° C., to give compounds of the formula III ##STR26## in whichR'₁ represents a protective group, R₇ represents in which B denotessubstituted alkyl, and R, R_(8-R) ₁₁, m and n have the above-mentionedmeanings. The reaction, product of the formula III is obtained from themixture by extraction with an organic solvent, washing the organic layerwith water, drying it over e.g. anhydrous sodium sulfate andconcentrating in vacuo. A chromatographic method may be used forpurification, if necessary.

Compounds of the formula III in which R'₁ represents a protective groupsuch as, for example, t-butyldimethylsilyl are treated with deprotectionreagents such as e.g. tetrabutylammonium fluoride in solvents such ase.g. THF or ether at temperatures in the range of about 0° to 30° C. inorder to obtain corresponding compounds of the formula I with R'₁ =H.

Compounds of the formula II are prepared by the process which isdescribed in EP-A 0,217,372 and J. Med. Chem. 31, 1872 (1988), fromcompounds of the formula IV ##STR27## in which R'₁ represents aprotective group such as t-butyl dimethyl silyl, and R represents avinyl group.

Compounds of the formula IV are prepared from forskolin (V) by thereaction sequence indicated below: ##STR28##

The 1-OH group in forskolin (V) is protected with a group R'₁, asdefined above, by methods known from the literature (cf. Reagents forOrg. Synth., L. F. Fieser and M. Fieser, John Wiley & Sons, Volumes 1 to11).

The acetyl group in the 7-position in compounds of the formula VI iseliminated by alkaline hydrolysis by methods described in the literature[cf. J.C.S. Perkin I, 769 (1982), and J. Med. Chem. 31, 1872 (1988)],which provides compounds of the formula IV.

Compounds of the formula 1 can also be obtained starting from compoundsof the formula lV. Compounds of the formula IV in which R'₁ has theabove menaing are treated with carboxylic acids of the formula R₁₃ R₁₄C═CH--COOH or R₁₂ ZCH₂ COOH in which R₁₂ --R₁₄ represent hydrogen or analkyl or substituted alkyl or aryl group or substituted aryl or aralkyl,wherein alkyl is preferably C₁ -C₄ -alkyl and aryl is preferably phenyl,in the presence of 4-dimethyl aminopyridine and DCC in organic solventssuch as e.g. dry dimethyl formamide or dry ethyl acetate, attemperatures in the range of about 20° to 30° C. for about four hours,and the products of the formula VII ##STR29## in which R₁₅ is ##STR30##or R₁₂ OCH₂ -- and R'₁ and R₁₂ -R₁₄ have the above meanings, areisolated from the raction mixture by dilution with water, subsequentextraction with organic solvents such as e.g. ethyl acetate, washing ofthe extract with water, drying over e.g. anhydrous sodium sulfate, andconcentration in vacuo. Chromatographic methods are used--ifnecessary--for purification J. Med. Chem. 31, 1872 (1988).

In order to obtain compounds of the formula VIII ##STR31## in which R'₁,R₁₅ have the above meanings, compounds of the formula VII aresubsequently treated with alkali such as sodium hydroxide inwater-soluble organic solvents such as acetonitrile [J. Med. Chem. 31,1872 (1988)].

Compounds of the formula VIII are subsequently treated with asubstituted organic acid of the formula R₁₆ COOH, such as e.g. methoxyacetic acid, ethoxy acetic acid, phenoxy acetic acid or p-chlorophenoxyacetic acid, phenyl acetic acid, acrylic acid or substituted acrylicacid in presence of DCC and 4-dimethylamino pyridine in organic solventssuch as e.g. dichloromethane, DMF or ethyl acetate, resulting incompounds of the formula IX in which one of R₁₅ or R₁₆ is R₁₃ R₁₄ C═CH--and the other is R₁₂ OCH₂ -- and wherein R'₁ and R₁₂ -R₁₄ have the abovemeanings. ##STR32##

Compounds of the formula IX are treated with the appropriate amine ofthe formula HNX₁ Y₁, in which X₁ and Y₁ have the above-mentionedmeanings, in an organic solvent such as e.g. dichloromethane, at atemperature of about 20° to 30° C. for about 16 to 24 hours. The productis obtained from the reaction mixture by extraction with an organicsolvent, washing of the extract with water, drying over e.g. anhydroussodium sulfate and concentration in vacuo. The compounds of the formulaI which still carry the protective group R'₁ are purified--ifnecessary--by column chromatography. The resulting compounds aredeprotected by deprotection reagents such as e.g. tetrabutylammoniumfluoride in solvents such as e.g. THF or ether at temperatures in therange of about 0° to 30° C. to give compounds of the formula I whereinR₁ is hydrogen.

The compounds according to the invention, and their salts exhibit usefuleffects on cardiovascular diseases, in particular, a selective positiveinotropic effect, and a lowering of the intraocular pressure. This isillustrated by the pharmacological investigations which follow and whichwere carried out to evaluate the compounds according to the invention,and their salts, and by the results obtained thereby.

POSITIVE INOTROPIC ACTIVITY

The following method was used:

Guinea pigs of both sexes and weighing 400 g are sacrificed, and theheart is removed and placed in Ringer's solution at room temperature.Both the left and the right atria are then isolated, fixed in an organholder and placed in a bath containing Ringer's solution and maintainedat a temperature of 32° C. A mixture of 95% O₂ and 5% CO₂ is bubbledthrough the organ bath. Electrical stimulation of the atrium is thencarried out. A compound according to the invention is dissolved in waterto give a solution of known concentration and is added to the bath. Thecontractility of the atrium is recorded for 7 to 10 minutes via anisomeric strain gage on a Nihon Kohden 4-channel pen recorder. Theactivity is expressed on the basis of the resulting data as the EC₅₀.

The results obtained in this model for representative compoundsaccording to the invention are listed in the table II. Data forcompounds disclosed in Indian Patent No. 163 242 are also provided forcomparison.

                  TABLE II                                                        ______________________________________                                         ##STR33##                                                                                                   Guinea                                                                        pig atrium                                     R.sub.6         R.sub.7        EC.sub.50 g/ml                                 ______________________________________                                         ##STR34##      COCH.sub.2 OC.sub.2 H.sub.5                                                                  0.044                                          .sup.a CO(CH.sub.2).sub.2 N(CH.sub.3).sub.2.2HCl                                              COCH.sub.2 OCH.sub.3                                                                         0.024                                          .sup.a COCH.sub.2 OCH.sub.3                                                                   CO(CH.sub.2).sub.2 NMe.sub.2.HCl                                                             0.77                                            ##STR35##      H              Not active                                      ##STR36##      H              1.8                                            ______________________________________                                         .sup.a Compounds of instant invention,                                        .sup.b Compounds of Indian Patent No. 163242.                            

Measurement of the intraocular pressure in conscious rabbits

For this experiment rabbits of both sexes and weighin 2 to 3 kg areused. The intraocular pressure (IOP) is measured with a Schioetztonometer after corneal anaesthesia with a 2% novocaine solution. A 2%solution of a compound according to the invention is prepared, using thestoichiometric amount of 0.1N HCl, by dissolving it or its salt directlyin water. After the initial value has been determined, 100 μl of thesolution of the test compound are distilled into one of the eyes, andthe vehicle is instilled into the other eye. The IOP is measured atdefined time intervals, i.e. 0.5, 1, 2, 3, 4 and 5 hours. The percentagedecreases in the IOP is calculated using the initial value.

The results obtained in this model for representative compoundsaccording to the invention are listed in the table III

                                      TABLE III                                   __________________________________________________________________________     ##STR37##                                                                                                IOP-Lowering Effect                               Compound              Dose  % decrease                                        R.sub.6        R.sub.7                                                                              percentage                                                                          in IOP                                                                              Duration                                    __________________________________________________________________________     ##STR38##     COCH.sub.2 OPh                                                                       2     31    300                                          ##STR39##     COCH.sub.2 OEt                                                                       2     31    >360                                         ##STR40##     COCH.sub.2 OEt                                                                       2     32    >360                                         ##STR41##     H      2     Not active                                        __________________________________________________________________________     .sup.a Compounds of instant invention,                                        .sup. b Compound from Indian Patent No. 163242.                          

The invention is illustrated by the examples which follow:

EXAMPLE 16β-Acryloyloxy-1α-t-butyldimethylsilyloxy-8,13-epoxy-9α-hydroxy-7β-methoxyacetoxy-labd-14-en-11-one

Methoxyacetic acid (0.53 ml, 6.92 mmol) was added to a mixture ofdicyclo hexylcarbodiimide (1.43 g, 6.92 mmol) and 4-dimethylaminopyridine (0.31 g, 2.54 mmol) in dry ethyl acetate (30 ml). The reactionmixture was stirred for 10 minutes at room temperature.6β-acryloyloxy-1α-t-butyldimethylsilyloxy-7β, 9α-dihydroxy-8,13epoxy-labd-14-en-11-one (1.27 g, 2.31 mmol) was added and stirred for 2hours. The excess dicyclohexylcarbodiimide in the reaction mixture wasdestroyed by adding water (5 ml). The stirring was continued at roomtemperature for 10 mins, and the mixture was subsequently filtered. Thefiltrate was washed with common salt solution. The organic layer wasdried over anhydrous sodium sulphate and evaporated. The residue waspurified by flash chromatography using ethyl acetate, petroleum ether(75:92.5) as eluant. Yield 90%, m.p. 144°-145° C.

Similarly, following compounds were prepared:

6β-Acryloyloxy-1α-t-butyldimethylsilyloxy-8,13-epoxy-7β-ethoxy-acetoxy-9α-hydroxylabd-14-en-11-one, m.p. 120°-121° C.

6β-Acryloyloxy-1α-t-butyldimethylsilyloxy-8,13-epoxy-9α-hydroxy-7β-phenylacetoxy-labd-14-en-11-one, m.p. 122°-123° C.

6β-Acryloyloxy-1α-t-butyldimethylsilyloxy-8,13-epoxy-9α-hydroxy-7β-phenoxyacetoxy-labd-14-en-11-one, m.p. 140° C.

6β-Acryloyloxy-1α-t-butyldimethylsilyloxy-8,13-epoxy-7β-(p-chlorophenoxy)-acetoxy-9α-hydroxylabd-14-en-11one,m.p. 168°-169° C.

7β-Acryloyloxy-1α-t-butyldimethylsilyloxy-8,13-epoxy-9α-hydroxy-6β-methoxyacetoxy-labd-14-en-11-one,m.p. 149° C.

1α-t-butyldimethylsilyloxy-6β,9α-dihydroxy-8,13-epoxy-7.beta.-methoxy-acetoxy-labd-14-en-11-one.

EXAMPLE 26β-Acryloyloxy-1α,9α-dihydroxy-8,13-epoxy-7β-methoxyacetoxy-labd-14-en-11-one

6β-Acryloyloxy-1α-t-butyldimethylsilyloxy-8,13-epoxy-9α-hydroxy-7β-methoxyacetoxy-labd-14-en-11-one(1.38 g, 2.28 mmol) in anhydrous tetrahydrofuran (30 ml) was stirredwith tetrabutyl ammonium fluoride trihydrate (0.81 g, 2.51 mmol) forhalf an hour at room temperature and the reaction mixture wasconcentrated. The residue was extracted with ethyl acetate, the organiclayer was washed with brine solution, dried over anhydrous sodiumsulphate and concentrated. The residue obtained was purified by flashchromatography using ethyl acetate:petroleum ether (1:4) as eluant. Thecompound was used as such for the next step. Yield 77%, m.p. 176°-178°C.

Similarly following compounds were prepared:

6β-Acryloyloxy-1α,9α-dihydroxy-8,13-epoxy-7β-ethoxyacetoxy-labd-14-en-11-one,m.p. 157°-158° C.

7β-Acryloyloxy-1α,9α-dihydroxy-8,13-epoxy-6β-methoxyacetoxy-labd-14-en.11-one,m.p. 194°-195° C.

EXAMPLE 31α,9α-Dihydroxy-6β-(3-N,N-dimethylamino-propionyloxy)-8,13-epoxy-7β-methoxy-acetoxy-labd-14-en-11-one

6β-Acryloyloxy-1α,9α-dihydroxy-8,13-epoxy-7β-methoxyacetoxy-labd-14-en-11-one(0.225 g, 0.47 mmol) was dissolved in dimethylamine in toluene (15 ml)and kept at 30° C. in a pressure vessel overnight. The reaction mixturewas concentrated in vacuo. The residue was purified by flashchromatography on silica gel using ethyl acetate:petroleumether:triethylamine (80:19:1) as eluant. Yield 40%, m.p. 169°-171° C.

Similarly, following compounds were prepared.

1α,9α-Dihydroxy-8,13-epoxy-6β-(3-N,N-dimethylamino-propionyloxy)-7β-ethoxyacetoxy-labd-14-en-11-one,m.p. 146°-147° C.

1α,9α-Dihydroxy-7β-(3-N,N-dimethylamino-propionyloxy)-8,13-epoxy-6β-methoxyacetoxy-labd-14 -en-11-one, m.p. 183°-184° C.

1α,9α-Dihydroxy-8,13-epoxy-6β-methoxyacetoxy-7β-(3-piperidino-propionyloxy)-labd-14-en-11-one,m.p. 209°-210° C.

1α,9α-Dihydroxy-8,13-epoxy-6β-methoxyacetoxy-7β-(3-morpholino-propionyloxy)-labd-14-en-11-one,m.p. 205°-206° C.

1α,9α-Dihydroxy-8,13-epoxy-6β-methoxyacetoxy-7β-(3-N-methylpiperazino-propionyloxy)-labd-14-en-11-one,m.p. 200°-201° C.

EXAMPLE 41α,9α-Dihydroxy-8,13-epoxy-7β-methoxyacetoxy-6β-(3-piperdidino-propionyloxy)-labd-14-en-11-one

Piperidine (1 ml) was added to a stirred solution of6β-acryloyloxy-1α,9α-dihydroxy-8,13-7β-methoxyacetoxy-labd-14-en-11-one(0.25 g, 0.506 mmol) in methylene chloride (10 ml). Stirring wascontinued overnight. The reaction mixture was concentrated under vacuoand the residue was purified by flash column chromatography using ethylacetate:petroleum ether: triethylamine (40:59:1) as eluant. Compound wasrecrystallised from ethyl acetate:petroleum ether. Yield 70%, m.p.136°-137° C.

Similarly following compounds were prepared:

1α,9α-Dihydroxy-8,13-epoxy-7β-methoxyacetoxy-6β-(3-morpholino-propionyloxy)-labd-14-en-11-one,m.p. 132°-133° C.

1α,9α-Dihydroxy-8,13-epoxy-7β-methoxyacetoxy-6β-(3-N-methyl-piperiazino-propionyloxy)-labd-14-en-11-one,m.p.

1α,9α-Dihydroxy-8,13-epoxy-7β-ethoxyacetoxy-6β-(3-piperidino-propionyloxy)-labd-14-en-11-one,m.p. 113°-114° C.

1α,9α-Dihydroxy-8,13-epoxy-7β-ethoxyacetoxy-6β-(3-morpholino-propionyloxy)-labd-14-en-11-one, m.p. 123°-124° C.

1α,9α-Dihydroxy-8,13-epoxy-7β-ethoxyacetoxy-6β-(3-N-methyl-piperazino-propionyloxy)-labd-14-en-11-one, m.p. 163°-164° C.

1α,9α-Dihydroxy-8,13-epoxy-7β-phenoxyacetoxy-6β-(3-piperidino-propionyloxy)-labd-14-en-11-one,m.p. 140°-141° C.

1α,9α-Dihydroxy-8,13-epoxy-7β-phenoxyacetoxy-6β-(3-morpholino-propionyloxy)-labd-14-en-11-one, m.p. 157°-158° C.

1α,9α-Dihydroxy-8,13-epoxy-7β-phenoxyacetoxy-6β-(3-N-methyl-piperazino-propionyloxy)-labd-14-en-11-one, m.p. 183°-184° C.

7β-p-chlorophenoxyacetoxy-1α,9α-dihydroxy-8,13-epoxy-6.beta.-(3-piperidino-propionyloxy)-labd-14-en-11-one,m.p. 151° C.

7β-p-chlorophenoxyacetoxy-1α,9α-dihydroxy-8,13-epoxy-6.beta.-(3-morpholino-propionyloxy)-labd-14-en-11-one,m.p. 151° C.

7β-p-chlorophenoxyacetoxy-1α,9α-dihydroxy-8,13-epoxy-6.beta.-(3-N-methyl-piperazinopropionyloxy)-labd-14-en-11-one, m.p. 203°-204° C.

Following compounds were prepared by using anhydrous dimethylamine intoiluene in place of piperidine:

1α,9α-Dihydroxy-6β-(3-N,N-dimethylaminopropionyloxy)-8,13-epoxy-7β-methoxyacetoxy-labd-14-en-11-one,m.p. 169°-171° C.

1α,9α-Dihydroxy-6β-(3-N,N-dimethylaminopropionyloxy)-8,13epoxy-7β-ethoxyacetoxy-labd-14-en-11-one,m.p. 146°-147° C.

1α,9α-Dihydroxy6β-(3-N,N-dimethylamino-propionyloxy)-8,13-epoxy-7β-phenoxyacetoxy-labd-14-en-11-one,m.p. 184°-185° C.

7β-p-Chlorophenoxyacetoxy-1α,9α-dihydroxy-6β-(3-N,N-dimethylaminopropionyloxy)-8,13-epoxy-labd-14-en-11-one,m.p. 153°-154° C.

EXAMPLE 51α-t-Butyldimethylsilyloxy-7β,9α-dihydroxy-8,13-epoxy-6.beta.-methoxyacetoxy-labd-14-en-11-one

1α-t-Butyldimethylsilyloxy-6β,9α-dihydroxy-8,13-epoxy-7.beta.-methoxyacetoxy-labd-14-en-11-one(12.3 g, 22.2 mmol) was added to a stirred mixture of acetonitrile (660ml), water (540 ml) and potassium carbonate (3.37 g, 24.42 mmol) at roomtemperature. Stirring was continued for 4 hours. The reaction mixturewas concentrated at low temperature (30°-35° C.) in vacuo. The residualmixture was extracted with ethyl acetate. The organic layer was Washedwith water followed by brine, dried over anhyd. sodium sulphate andconcentrated. The residue was purified by chromatography over silica gelusing ethyl acetate:diisopropyl ether: petroleum ether (1:1:3) as eluantyield 8.3 g.

EXAMPLE 6 General Method for Preparation of Hydrochloride Salts

Diethyl ether saturated with dry HCl gas was added to the methanolicsolution of the compound (prepared in Example3 and 4) at 0° C. Thereaction mixture was further diluted with diethyl ether and filtered.The precipitate thus obtained was filtered and crystallized withmethanol:diethyl ether and gave the corresponding hydrochloride salts(listed in Table I).

We claim:
 1. A compound having the formula ##STR42## wherein R isvinyl;R₁ is hydrogen; R₆ is --CO(CH₂)₂ NX₁ Y₁, wherein X₁ and Y₁ areeach methyl or X₁ and Y₁ form, together with the N atom to which theyare bonded, a piperidine, morpholine, or N-methylpiperazine ring; and R₇is --COCH₂ OZ₁, wherein Z₁ is methyl, ethyl, phenyl, or4-chlorophenyl;and the optical and geometric isomers andpharmaceutically acceptable salts thereof.
 2. A compound having theformula ##STR43## wherein R is vinyl;R₁ is hydrogen; R₆ is --COCH₂ OCH₃; and R₇ is --CO(CH₂)₂ NX₁ Y₁, wherein X₁ and Y₁ are each methyl or X₁and Y₁ form, together with the N atom to which they are bonded, apiperidine, morpholine, or N-methylpiperazine ring;and the optical andgeometric isomers and pharmaceutically acceptable salts thereof. 3.Process for the manufacture of a compound as claimed in claim 1, whichcomprises splitting off the protective group R'₁ from compounds of theformula ##STR44## and the optical and geometric isomers andpharmaceutically acceptable salts thereof.
 4. Process for themanufacture of a compound as claimed in claim 2, which comprisessplitting off the protective group R'₁ from compounds of the formula##STR45## and the optical and geometric isomers and pharmaceuticallyacceptable salts thereof.
 5. A method of treating cardiovasculardiseases selected from the group consisting of congestivecardiomyopathy, hypertension, and thrombosis, which comprisesadministering to a host in need thereof a compound according to claim 1in an amount effective to treat cardiovascular diseases.
 6. A method oftreating cardiovascular diseases selected from the group consisting ofcongestive cardiomyopathy, hypertension, and thrombosis, which comprisesadministering to a host in need thereof a compound according to claim 2in an amount effective to treat cardiovascular diseases.
 7. A method oflowering intraocular pressure, which comprises administering to a hostin need thereof a compound according to claim 1 in an amount effectiveto lower intraocular pressure.
 8. A method of lowering intraocularpressure, which comprises administering to a host in need thereof acompound according to claim 2 in an amount effective to lowerintraocular pressure.